Drug delivery system comprising a volume increasing matrix containing a plurality of tiny pills

ABSTRACT

A delivery device is disclosed for delivering a beneficial drug to a biological environment of use. The device comprises a hydrogel reservoir containing tiny pills. The tiny pills comprise a wall surrounding a drug core.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Pat. Appln. Ser. No.06/571,299, filed Jan. 16, 1984 now U.S. Pat. No. 4,649,043 issued Mar.10, 1987 which Appln. Ser. No. 06/571,299 is a continuation of U.S. Pat.Appln. Ser. No. 06/360,477 filed Mar. 22, 1982 now U.S. Pat. No.4,434,153 issued Feb. 28, 1984, which Appln. Ser. No. 06/571,299 iscopending with U.S. Pat. Appln. Ser. No. 06/571,618 filed Jan. 1, 1984now U.S. Pat. No. 4,659,558 issued Apr. 21, 1987 and is copending withU.S. Pat. Appln. Ser. No. 06/571,009 filed Jan. 16, 1984, now U.S. Pat.No. 4,642,233 issued Feb. 10, 1987. These applications are incorporatedherein by reference and benefit is claimed of their filing dates. Theseapplications are assigned to ALZA Corporation of Palo Alto, CA.

FIELD OF THE INVENTION

This invention pertains to a drug delivery system manufactured in theform of a drug delivery device. More particularly, the inventionpertains to a drug delivery device for remaining in the stomach over aprolonged period of time, and it comprises a reservoir formed of anexpandable material containing a plurality of tiny pills.

BACKGROUND OF THE INVENTION

A long-felt need exists for a drug delivery system for remaining in thestomach over a prolonged period of time. The need exists for a drugdelivery system that remains in the stomach and acts as an in vivoreservoir that releases drug at a controlled rate and continuously for(a) absorption in the stomach, or for (b) passage into the intestine forabsorption therein. Drug delivery systems are used clinically foradministering a drug for its beneficial effect. Often the drug isadministered from (1) a delivery system that releases a drug as thesystem moves through the gastrointestinal tract over time, or from (2) adelivery system that remains in the stomach and releases drug while inthe stomach. The delivery systems are used because they eliminate theneed for administering a number of single doses at periodic intervals.The convenience of using a drug delivery system, which releases drugover a prolonged period of time as opposed to the administration of anumber of doses, has long been recognized in the practice of medicine.The preferred sought-after therapeutic advantage to the patient and theclinician is controlled and optimum blood levels of drug during theperiod of time drug is released from the delivery system. This advantagearises from the delivery system continuously supplying drug for itspassage and absorption into the blood for replacing drug used,eliminated, or metabolically inactivated by the patient.

The above presentation teaches that delivery systems have been providedfor continuously supplying drug for obtaining better therapy in themanagement of health and disease. For example, one system used forcontinuously releasing drug over a long period of time is disclosed bypatentee Blythe in U.S. Pat. No. 2,738,303. The delivery systemdisclosed in this patent consists essentially of a capsule containinguncoated pellets of drug and coated pellets of drug having varyingthickness. On their release from the capsule, the uncoated pelletsprovide an initial amount of drug and the coated pellets provide drugover a period of time. Another delivery system is disclosed by patenteesSheth et al in U.S. Pat. Nos. 4,140,775 and 4,167,558. The systemsdisclosed in these latter patents consists essentially of a tabletformed of a compressed polymer containing dispersed drug. The system ishydrodynamically balanced for remaining in the stomach for releasingdrug therein over time.

While the above delivery systems are designed for providing a continuoussupply of drug, there are inherent short-comings associated with thesedelivery systems. For example, pellets often pass through thegastrointestinal tract quickly, and this tends to limit their supplyingof drug needed for maintaining a desired blood level of drug. Also,pellets are not designed for remaining in the stomach over an extendedperiod of time as they tend to empty from the stomach in a first ordermanner like liquids. The tablet, on its exposure to stomach fluid,releases drug by uncontrolled leaching action and at a declining rate,which actions restrict the use of the tablet as a controlled deliverysystem during the time of its residency in the stomach.

It will be appreciated by those versed in the drug dispensing art inview of the above presentation, that if a delivery system is providedthat remains in the stomach and acts as an in vivo drug reservoir whileconcurrently releases drug in the stomach for (a) absorption in thestomach, or for (b) passage into the intestine for absorption therein,essentially without disrupting the normal emptying of ingested foods andliquids, such a delivery system would have a positive value andrepresent a substantial contribution to the dispensing art. Likewise, itwill be appreciated by those skilled in the art, that if a deliverysystem is made available that remains in the stomach for releasing drugat a controlled rate over time for achieving therapeutic blood levels,such a delivery system would be clinically useful in the practice ofmedicine.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation it is an immediate objectof this invention to provide a novel and useful drug delivery systemthat satisfies the long-felt need and overcomes the short-comings knownto the prior art.

Another object of the invention is to provide a drug delivery devicethat is simple in construction and which device exhibits all of thepractical benefits of controlled and continuous administration of drugto animals and humans over a prolonged period of time.

Another object of the invention is to provide a drug delivery systemmanufactured in the form of a drug delivery device for prolongedresidency in the stomach for executing a therapeutic program therein.

Still another object of the invention is to provide a drug deliverydevice comprising a reservoir formed of an expandable materialcontaining tiny pills, which device is useful for maintaining thestomach in the fed mode and/or for concomitantly keeping the housekeeperaway for extending the stomach residence of the drug delivery device.

Yet another object of the invention is to provide a drug delivery devicecomprising a swellable reservoir containing tiny pills for remaining inthe stomach an extended period of time for making a drug availabletherein, or for its subsequent passage into the intestine.

Yet still another object of the invention is to provide a drug deliverydevice that by its size will be retained in the stomach during the fedmode, and prior to its passage into the small intestine bioerodes in thestomach over time.

Yet still another object of the invention is to provide a drug deliverydevice dimensioned to be retained in the stomach for delivering drug inthe stomach and hence into the intestine.

These objects, as well as other objects, features and advantages of theinvention, will become more apparent from the following detaileddescription of the invention, the drawings, and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is a view of an oral drug delivery device provided by theinvention;

FIG. 2 is an opened view in cross-section through 2--2 of FIG. 1;

FIG. 3 is an expanded, swelled view of FIG. 2; and,

FIG. 4 depicts a multiplicity of tiny pills, some in cross-section onthe release from the delivery device of FIGS. 1 to 3.

In the drawings and specifications, like parts in related Figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are an example of variousdrug delivery device provided by the invention, and which example is notto be construed as limiting, one example of a drug delivery device isseen in FIGS. 1 through 3, considered together, and indicated by numeral10. In FIGS. 1 through 3, device 10 is seen comprising a body 11 that isadapted, shaped and sized for oral admittance into the gastrointestionaltract for extended residency in the stomach. In FIGS. 2 and 3, seen inopened section, body 11 comprises a reservoir 12 formed of a non-toxicmaterial that expands and swells in the presence of fluid in theenvironment of use, such as water or gastric fluid. The material formingreservoir 12 in a presently preferred embodiment is a hydrophilicpolymer, such as a hydrogel. In FIG. 2, reservoir 12 made of ahydrophilic material is illustrated in a non-hydrated state. In FIG. 3reservoir 12 is illustrated in an enlarged state as the material absorbsand imbibs fluid from the environment of use and swells or expands tosome equilibrium state. This increase in size acts as a means forretaining device 10 in the stomach over an extended period of time.Reservoir 12 leaves the environment of use by hydrolyzing or bioerodingduring and at the end of the drug delivery period. A description ofmaterials useful for forming reservoir 12 appears later in thespecification.

Drug delivery device 10 of FIGS. 1 through 3, seen in opened view inFIGS. 2 and 3, houses a multiplicity of tiny pills 13 for the controlleddelivery of drug over time. In FIG. 4, tiny pills 13 are seen in detail,and they comprise a core of drug 14 surrounded by a wall 15 formed of arelease rate controlling material. Tiny pills 13 can have wall 15 madefrom a material that releases drug 13 in the stomach, or tiny pill 13can have a wall 15 made from an enteric material which prevents releaseof drug 14 in the stomach, but will release drug 14 in the intestine.Additionally, the materials forming wall 15 can be selected frommaterials that release drug 14 by different physical-chemicalmechanisms. These mechanisms include erosion, diffusion, osmosis,metabolism, and the like. Wall 15 can have various thicknesses as anadditional aid for providing timed release of drug. A description ofwall forming materials appears later in the specification.

In operation, device 10 resides in the stomach for an extended period oftime by concurrently (1) enlarging in the stomach, and by (2) keepingthe stomach in the fed mode. Device 10 delivers drug 14 (a) in thestomach by nonenteric coated tiny pills 13 releasing drug over time, and(b) in the intestine by device 10 releasing enteric coated tiny pills 13for their passage into the intestine wherein tiny pills 13 deliver drug14 over a prolonged period of time.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, delivery device 10 canbe made with a reservoir 12 of a material that does not adversely affectdrug 14, an animal or other host. The presently preferred materialsuseful for forming reservoir 12 comprise hydrogels that exhibit theability to swell in water and retain a significant fraction of waterwithin its structure. The hydrogels can be noncrosslinked or they may becross-linked with acid mobile covalent or ionic bonds sensitive to slowacidic hydrolysis. The hydrogels can be of plant or animal origin,hydrogels prepared by modifying naturally occuring structures, andsynthetic polymeric hydrogels. The polymeric hydrogels swell or expandto a very high degree, usually exhibiting a 2 to 50 fold volumeincrease. Hydrophilic polymeric materials useful for the purpose includepoly(hydroxyalkyl methacrylate), poly(electrolyte comple es), poly(vinylacetate) cross-linked with hydrolysable bonds, water-swellable N-vinyllactams polysaccharides, natural gum, agar, agrose, sodium alginate,carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gumarabic, gum ghatti, gum karaya, gum tragacanth, locust beam gum,arbinoglactan, pectin, amylopectin, gelatin, hydrophilic colloids suchas carboxymethyl cellulose gum or alginate gum cross-linked with apolyol such as propylene glycol, and the like.

Other hydrogels include hydrophilic hydrogels known as Carbopol® acidiccarboxy polymer, Cyanamer® polyacrylamides, Good-rite® polyacrylic acid,polyethylene oxide, starch graft copolymers, Aqua-Keeps® acrylatepolymer, ester cross-linked polyglucan, and the like. The hydrogels areknown to the prior art in U.S. Pat. Nos. 3,640,741; 3,865,108;3,992,562; 4,002,173; 4,014,335; and 4,207,893; and in Handbook ofCommon Polymers, by Scott and Roff, published by the Chemical RubberCompany; Cleveland, Ohio.

Wall 15 of tiny pill 13 surrounding drug 14 can be a wall-formingcomposition consisting essentially of a fatty ester mixed with a wax,such as a triglyceryl ester selected from the group consisting ofglyceryl distearate, glyceryl tristearate, glyceryl monostearate,glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate,glyceryl didocosanoate, glyceryl tridocosanoate, glycerylmonodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryltricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryltrimyristate, glyceryl monodecenoate, glyceryl didecenoate and glyceryltridecenoate.

The wax included in the wall forming composition is a member selectedfrom the group consisting essentially of beeswax, cetyl palmitate,spermacetic wax, carnauba wax, cetyl myristate, cetyl palmitate, cerylcerotate, stearyl palmitate, stearyl myristate and lauryl laurate.

The composition comprising the ester and the wax can be coated aroundthe drug by using an organic solvent such as a member selected from thegroup consisting of carbon tetrachloride, chloroform, trichloroethylene,ether, benzene, ethyl acetate, methyl ethyl ketone, isopropyl alcohol,and the like. The fatty esters, waxes, solvents and procedures formaking tiny pills that slowly disintegrate and continuously provide drugover a period of 10 to 12 hours are disclosed in U.S. Pat. No.2,793,979.

Wall 15 of tiny pills 13 in another embodiment is formed of an osmoticwall forming material that releases drug 14 at a controlled rate by theprocess of osmotic bursting over time. Drug 14 in this embodiment ispresent in the form of an osmotic solute, such as a therapeuticallyacceptable salt, and it exhibits an osmotic pressure gradient acrosswall 15 against an external fluid. The membrane material used to formwall 15 are those permeable to the passage of an external fluid andsubstantially impermeable to the passage of drug. Typical materialsinclude a member selected from the group consisting of celluloseacylate, cellulose diacylate, cellulose triacylate, cellulose acetate,cellulose diacetate, cellulose triacetate, cellulose acetate having adegree of substitution, D.S., up to 1 and an acetyl content of 21%,cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21to 35%, cellulose triacetate having a D.S. of 2 to 3 and an acetylcontent of 35 to 44.8%, cellulose acetyl propionate, cellulose acetatebutyrate, and the like. The osmotic wall can be coated around the drugin varying thickness by pan coating, spray-pan coating, Wurster fluidair-suspension coating and the like. The wall is formed using organicsolvents, including those mentioned above, and solvent systems such asmethylene chloride-methanol, methylene chloride-acetone,methanol-acetone, ethylene dichloride-acetone, and the like. Osmoticwall forming material, procedures for forming the wall, and osmoticbursting procedures are disclosed in U.S. Pat. Nos. 2,799,241;3,952,741; 4,014,334; and 4,016,880.

Wall 15 in another embodiment can be made of a drug release ratecontrolling material. That is, drug 14 dissolves in the wall and passesthrough the wall at a controlled rate over time. Exemplary materialsuseful for forming a diffusional wall include ethylene-vinyl acetate,ethyl cellulose, polyethylene, cross-linked polyvinyl pyrrolidone,vinylidene chloride-acrylonitrile copolymer, polypropylene, silicone,and the like. The wall can be applied by the techniques described above,and materials suitable for forming wall 15 are described in U.S. Pat.Nos. 3,938,515; 3,948,262; and 4,014,335.

Wall 15 in still another embodiment can be made of a bioerodiblematerial that bioerodes at a controlled rate and releases drug 14 to thebiological environment of use. Bioerodible materials useful for formingwall 15 include polyvalent acid or alkali mobile cross-linkedpolyelectrolytes, polycarboxylic acid, polyesters, polyamides,polyimides, polylactic acid, polyglycolic acid, polyorthoesters, andpolyorthocarbonates. The polymers and procedures for forming wall 15 aredisclosed in U.S. Pat. Nos. 3,811,444; 3,867,519; 3,888,975; 3,971,367;3,993,057; and 4,138,344.

In the specification and the accompanying claims the term drug includespharmacologically active substances that produce a local or systemiceffect in animals, which term includes warm-blooded mammals such ashumans. The active drug that can be delivered includes drugs that act onthe central nervous system, depressants, hypnotics, sedatives, psychicenergizers, tranquilizers, anticonvulsants, muscle relaxants,antiparkinson agents, analgesics, anti-inflammatory, hormonal agents,contraceptives, sympathomimetics, diuretics, anti-parasites,neoplastics, hypoglycemics, ophthalmics, electrolytes, cardiovasculardrugs, and the like.

Exemplary drugs that are soluble in water and can be delivered by thedevices of this invention include prochlorperazine edisylate, ferroussulfate, aminocaproic acid, potassium chloride, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,benzhetamine hydrochloride, isoproternol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, atropine sulfate, methascopolamine bromide,isopropamide iodide, tridihexethyl chloride, oxprenolol hydrochloride,metoprolol hydrochloride, cimetidine hydrochloride, and the like.

Exemplary drugs that have limited solubility in water and can bedelivered by devices of this invention include meclizine hydrochloride,phenoxybenzamine, thiethylperazine maleate, anisindone, erythrityltitranitrate, dizoxin, reserpine, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin,progestins, estroginie, progestational, corticosteroids, and the like.

Examples of other drugs that can be delivered by the devices includeaspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac,indoprofen, propranolol, metoprolol, oxprenolol, timolol, clonidine,theophylline, ferrous lactate, phenoxybenzamine, baclofen, furosemide,and the like. The beneficial drugs are known in the art inPharmaceutical Sciences, by Remington, 14th Ed., 1979, published by MackPublishing Co.; The Drug, The Nurse, The Patient, Including Current DrugHandbook, by Falconer et al., 1974-1976, published by Saunder Company;and Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by Burger, published byWiley-Interscience Co.

The drug can be present in the tiny pill in various forms, such asunchanged molecules, molecular complexes, therapeutically acceptablesalts such as hydrochlorides, hydrobromides, sulfates, oleates, and thelike. For acid drugs, salts of metals, amines, or organic cations,quaternary ammonium salts can be used. Derivatives of drugs such asesters, ethers and amides can be used. Also, a drug that is waterinsoluble can be used in a form that is the water soluble derivativethereof to serve as a solute, and on its release from the device, isconverted by enzymes, hydrolyzed by body pH, or other metabolicprocesses to the original biologically active form. The amount of drugpresent in a tiny timed pill generally is about 10 mg to 20 mg, and thenumber of tiny pills in an oral device is about 10 to 1000, preferably100 to 150. The tiny pills comprising the wall and inner core of drughave a diameter of at least 100 microns and in a presently preferredembodiment a diameter of at least 2000 microns. For oral use, thedelivery device comprising the reservoir and the tiny pills homogenouslyor heterogenously housed therein, can have conventional shapes such asround, oval and the like. The device can have a diameter of 3/16 inchesto 1/2 inches and the like.

The following examples will further serve to illustrate the invention.An orally administrable tablet containing tiny pills of asympathomimetic drug is prepared as follows: powdered drug is mixed withsucrose and the blend passed through a 15 to 30 mesh screen to yield amultiplicity of cores of drug. Then, a wall-forming compositioncomprising 85% glycerol monostearate and 15% beeswax in warm carbontetrachloride is sprayed over cores in a revolving coating pan until awall is formed that individually surrounds the cores. Next, after thecoating is stripped from the tiny pills, a series of oral tablets areprepared by blending about 50 tiny pills with about 200 mg of groundreservoir forming carboxy-vinyl polymer, commercially available asCarbopol® polymer, and then pressing the latter blend in a tabletingmachine under a pressure of 4 kg to yield the delivery device.

Additional drug delivery devices are provided by coating a drug core,for example, procainamide hydrochloride, in a fluid air suspensionmachine with a composition of ethylcellulose in ethanol to surround thedrug with a wall of procainamide hydrochloride, yielding tiny pillsthereof. After the solvent is vacuum stripped from the tiny pills, theyare blended with ground lightly crosslinked polyacrylamide and pressedinto an oral tablet.

The above manufacture can be repeated by replacing the ethylcelluloseand ethanol with cellulose acetate having an acetyl content of 32% andmethylene chloride-methanol solvent; or by applying a bioerodible wallof poly(2,2-dioxotrans-1,4-cyclohexane dimethylene tetrahydrofuran)around the tiny pills. The latter polymer is applied by heating thepolymer to 80-90 C. and then dispersing the tiny pills in the polymer.

In another example, a delivery device is made by first preparingsustained release tiny pills by blending 400 ml of ethylcellulose-water, 70:30%, solution, 7.5% w:v, with 375 g of theophylline,150 g of mannitol and 475 g of magnesium stearate and the blend kneadedand passed through an extrusion granulation machine. After drying at115°-120° F., the cores are passed through a 20 mesh screen and coatedwith a wall of ethyl cellulose in an air suspension machine to yeildtiny timed pills. Next, a multiplicity of tiny pills are blended with ahydrogel reservoir forming polymer consisting essentially of a coherentmeshwork that imbibs and immobilizes water, powdered alginate gumcrossed-linked with propylene glycol, and the mixture is compressed in atablet machine using 11/32 inch deep concave punch to yield the drugdelivery device for orally administering as a bronchodilator in themanagement of status asthmaticus, and as a pulmonary vasodilator andsmooth muscle relaxant. Other forms of theophylline can be used in thesubject delivery device such as theophylline sodium acetate,theophylline sodium glycinate, [7-(2,3-dihydroxypropyl)]theophylline,theophylline meglumine and theophylline monoethanolamine.

Other drug delivery systems are made by spraying non-pareil cores withan edible adhesive and then dusting with drug. The drug-coated core iscoated with an appropriate number of edible enteric coatings to giveenteric coated tiny pills. The number of enteric coats is variable,usually at least 1 to 10 separate coats are used for the presentpurpose. Finally, the tiny pills are housed in the hydrogel reservoir.Manufacturing procedures for the tiny pill are taught in U.S. Pat. No.3,365,365. Also, the tiny pills can be made from a core of carbohydrate,such as sucrose, dusted wit with a mixture of talc, starch andgalactose, moistened with distilled or deionized water, and then dustedwith the desired medicinal, such as the antibiotic erythromycin. Thepills are dried and then coated with an outer layer of a non-toxic,acidic, enteric wall formerly selected from the group consisting ofkeratin, calcium alginate, shellac, partially hydrolyzed styrene-maleicacid copolymer, polyvinylacitate phthalate, polyvinyl hydrogenphthalate,and the like. Finally, the tiny pills are dispersed in a hydrogelreservoir matrix sized, shaped and adapted for oral admittance into thegastrointestional tract. Procedures for manufacturing the tiny pills aredisclosed in U.S. Pat. No. 3,081,233.

It will be appreciated by those versed in the art, the present inventionmakes available novel and useful delivery devices for dispensing abeneficial drug over a prolonged period of time. Also, it will beunderstood by those knowledged in the dispensing art, that manyembodiments of this invention can be made without departing from thespirit and scope of the invention, and the invention is not to beconstrued as limited, as it embraces all equivalents therein.

We claim:
 1. A tablet dosage form for the controlled delivery of anorally administrable beneficial drug to the gastrointestinal tract forexecuting a therapeutic program over a prolonged period of time, thetablet dosage form comprising:(1) a tablet matrix hydrogel which absorbsand imbibes water, and swells and expands and increases in size orvolume, and, in the expanded state, acts as a means for stomachretention for an extended period of time comprising a pharmaceuticallyacceptable starch fraft copolymer composition; and, (2) a plurality oftiny pills housed throughout the tablet matrix, the tiny pillscomprising:(a) a dosage amount of an orally administrable beneficialdrug; and, (b) a wall surrounding the drug, the wall comprising acellulose composition selected from the group consisting of celluloseacylate, cellulose diacylate, cellulose triacylate and ethyl cellulose.